When Bad Prions Go Good

Long-term memory may depend on molecules that are oddly similar to prions, a sinister group of proteins believed to cause mad cow disease. Kausik Si and Nobel laureate Eric Kandel of Columbia University claim that the property that makes prions so deadly—their ability to set off a chain reaction of protein shape-shifting—allows our brains to store thoughts for a lifetime.

Si was studying CPEB, a protein that helps activate neural connections during memory formation, when he noticed that the tail of the molecule resembled a prion. Curious, he engineered CPEB into yeast cells to see what would happen. In its new environment the protein acted just like a prion: It folded itself into a new shape and caused neighboring proteins to do the same. But the shape-shifted molecules didn’t become garbage, as happens when prions misfold to cause diseases like mad cow. Instead, the changed CPEB became a fast-replicating, active version of its normally dormant form.

“This suggests there is a normal role for prionlike proteins in the brain,” Si says. He speculates that transient electrical signals flip dormant CPEB into their high-activity, prionlike state as part of memory formation. “The fact that the process is self-perpetuating makes the new connections very stable,” he says. His work may not lead to a cure for prion diseases, but it gives us a better idea of how they work. Mad cow prions are found all over the body, but they cause problems only in the brain. The problem, Si speculates, is that neurons provide a prion-friendly environment because similar proteins operate there all the time.